EP1267934A2 - Neues verfahren zur diagnose, überwachung, statusbestimmung, bildmässiger darstellung und behandlung von brustkrebs - Google Patents
Neues verfahren zur diagnose, überwachung, statusbestimmung, bildmässiger darstellung und behandlung von brustkrebsInfo
- Publication number
- EP1267934A2 EP1267934A2 EP00980657A EP00980657A EP1267934A2 EP 1267934 A2 EP1267934 A2 EP 1267934A2 EP 00980657 A EP00980657 A EP 00980657A EP 00980657 A EP00980657 A EP 00980657A EP 1267934 A2 EP1267934 A2 EP 1267934A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- bcsg
- breast cancer
- patient
- levels
- cells
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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- A—HUMAN NECESSITIES
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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/136—Screening for pharmacological compounds
Definitions
- This invention relates, in part, to newly identified breast cancer specific genes and assays for detecting, diagnosing, monitoring, staging, prognosticating, imaging and treating cancers, particularly breast cancer.
- breast cancer patients are closely monitored following initial therapy and during adjuvant therapy to determine response to therapy and to detect persistent or recurrent disease or metastasis.
- Another important step in managing breast cancer is to determine the stage of the patient's disease. Stage determination has potential prognostic value and provides criteria for designing optimal therapy.
- pathological staging of cancer is preferable over clinical staging because the former gives a more accurate prognosis.
- clinical staging would be preferred were it at least as accurate as pathological staging because it does not depend on an invasive procedure to obtain tissue for pathological evaluation. Staging of cancer would be improved by detecting new markers in cells, tissues or bodily fluids which could differentiate between different stages of invasion.
- BCSGs New breast cancer specific genes, referred to herein as BCSGs , have now been identified for use in diagnosing, monitoring, staging, imaging and treating cancers, and in particular breast cancer. Accordingly, the present invention relates to new methods for detecting, diagnosing, monitoring, staging, prognosticating, in vivo imaging and treating cancer via a BCSG.
- BCSG refers, among other things, to native proteins expressed by the genes comprising the polynucleotide sequences of BCSG-1 or Gene ID 332369 (SEQ ID NO: 1) , BCSG-2 or Gene ID 480489 (SEQ ID NO : 2 or 18), BCSG-3 or Gene ID 274731 (SEQ ID NO : 3 or 20), BCSG-4 or Gene ID 173388 (SEQ ID NO:4) or BCSG-5 or Clone ID 3040232, Gene ID 411152 (SEQ ID NO: 5) .
- Exemplary proteins expressed by genes BCSG-2 and BCSG- 3 are depicted herein as SEQ ID NO: 19 and SEQ ID NO: 21.
- BCSG it is also meant herein variant polynucleotides which, due to degeneracy in genetic coding, comprise variations in nucleotide sequence as compared to SEQ ID NO: 1, 2, 3, 4, 5, 18 or 20 but which still encode the same proteins.
- BCSG means the native mRNAs encoded by the genes comprising BCSG-1 or Gene ID 332369 (SEQ ID NO: 1) , BCSG-2 or Gene ID 480489 (SEQ ID NO:2 or 18), BCSG-3 or Gene ID 274731 (SEQ ID NO : 3 or 20), BCSG-4 or Gene ID 173388 (SEQ ID NO:4) or BCSG-5 or Clone ID 3040232, Gene ID 411152 (SEQ ID NO:5) or it can refer to the actual genes comprising BCSG-1 or Gene ID 332369 (SEQ ID NO:
- BCSG-2 or Gene ID 480489 SEQ ID NO:2 or 18
- SEQ ID NO:4 or BCSG-5 or Clone ID 3040232, Gene ID 411152 (SEQ ID NO:5), or levels of polynucleotides which are capable of hybridizing under stringent conditions to the antisense sequences of SEQ ID NO : 1, 2, 3, 4, 5, 18 or 20.
- BCSGs comprising a polynucleotide of SEQ ID NO:l, 2, 3, 4, 5, 18 or 20 or a variant thereof, a protein expressed by a polynucleotide of SEQ ID NO : 1 , 2, 3, 4, 5, 18 or 20 or variant thereof which expresses the protein; or a polynucleotide which is capable of hybridizing under stringent conditions to the antisense sequence of SEQ ID NO: 1, 2, 3, 4, 5, 18 or 20.
- a method for diagnosing the presence of breast cancer by analyzing for changes in levels of BCSG in cells, tissues or bodily fluids compared with levels of BCSG in preferably the same cells, tissues, or bodily fluid type of a normal human control, wherein a change in levels of BCSG in the patient versus the normal human control is associated with breast cancer.
- a method of diagnosing metastatic breast cancer in a patient having breast cancer which is not known to have metastasized by identifying a human patient suspected of having breast cancer that has metastasized; analyzing a sample of cells, tissues, or bodily fluid from such patient for BCSG; comparing the BCSG levels in such cells, tissues, or bodily fluid with levels of BCSG in preferably the same cells, tissues, or bodily fluid type of a normal human control, wherein an increase in BCSG levels in the patient versus the normal human control is associated with breast cancer which has metastasized.
- Also provided by the invention is a method of staging breast cancer in a human by identifying a human patient having breast cancer; analyzing a sample of cells, tissues, or bodily fluid from such patient for BCSG; comparing BCSG levels in such cells, tissues, or bodily fluid with levels of BCSG in preferably the same cells, tissues, or bodily fluid type of a normal human control, wherein an increase in BCSG levels in the patient versus the normal human control is associated with a cancer which is progressing and a decrease in the levels of BCSG is associated with a cancer which is regressing or in remission.
- a method of monitoring breast cancer in a human patient for the onset of metastasis comprises identifying a human patient having breast cancer that is not known to have metastasized; periodically analyzing cells, tissues, or bodily fluid from such patient for BCSG; comparing the BCSG levels in such cells, tissue, or bodily fluid with levels of BCSG in preferably the same cells, tissues, or bodily fluid type of a normal human control, wherein an increase in BCSG levels in the patient versus the normal human control is associated with a cancer which has metastasized.
- the method comprises identifying a human patient having breast cancer; periodically analyzing cells, tissues, or bodily fluid from such patient for BCSG; comparing the BCSG levels in such cells, tissue, or bodily fluid with levels of BCSG in preferably the same cells, tissues, or bodily fluid type of a normal human control, wherein an increase in BCSG levels in the patient versus the normal human control is associated with breast cancer which is progressing and a decrease in the levels of BCSG is associated with breast cancer which is regressing or in remission.
- therapeutic agents such as antibodies targeted against a BCSG or fragments of such antibodies can be used to treat, detect or image localization of a BCSG in a patient for the purpose of detecting or diagnosing a disease or condition.
- an increase in the amount of labeled antibody detected as compared to normal tissue would be indicative of tumor metastases or growth.
- Such antibodies can be polyclonal, monoclonal, or omniclonal or prepared by molecular biology techniques.
- antibody as used herein and throughout the instant specification is also meant to include aptamers and single-stranded oligonucleotides such as those derived from an in vi tro evolution protocol referred to as SELEX and well known to those skilled in the art.
- Antibodies can be labeled with a variety of detectable labels including, but not limited to, radioisotopes and paramagnetic metals.
- Therapeutics agents such as small molecule and antibodies or fragments thereof which decrease the concentration and/or activity of a BCSG can also be used in the treatment of diseases characterized by overexpression of BCSG. In these applications, the antibody can be used without or with derivatization to a cytotoxic agent such as a radioisotope, enzyme, toxin, drug or a prodrug.
- the present invention relates to diagnostic assays and methods, both quantitative and qualitative for detecting, diagnosing, monitoring, staging, prognosticating, in vivo imaging and treating breast cancer by comparing levels of breast cancer specific genes (BCSGs) with levels of BCSGs in a normal human control.
- BCSGs breast cancer specific genes
- BCSG refers, among other things, to native proteins expressed by the genes comprising the polynucleotide sequences of BCSG-1 or Gene ID 332369 (SEQ ID NO: 1), BCSG-2 or Gene ID 480489 (SEQ ID NO : 2 or 18), BCSG-3 or Gene ID 274731 (SEQ ID NO : 3 or 20), BCSG-4 or Gene ID 173388 (SEQ ID NO : 4 ) or BCSG-5 or Clone ID 3040232, Gene ID 411152 (SEQ ID NO: 5) .
- Exemplary proteins expressed by genes BCSG-2 and BCSG-3 are depicted herein as SEQ ID NO: 19 and SEQ ID NO: 21.
- BCSG means the native mRNAs encoded by the genes comprising BCSG-1 or Gene ID 332369 (SEQ ID NO: 1) , BCSG-2 or Gene ID 480489 (SEQ ID NO : 2 or 18), BCSG-3 or Gene ID 274731 (SEQ ID NO : 3 or 20), BCSG-4 or Gene ID 173388 (SEQ ID NO:4) or BCSG-5 or Clone ID 3040232, Gene ID 411152 (SEQ ID NO: 5) or it can refer to the actual genes comprising BCSG-1 or Gene ID 332369 (SEQ ID NO: 1) , BCSG-2 or Gene ID 480489
- a diagnostic assay in accordance with the invention for diagnosing over-expression of a BCSG protein compared to normal control bodily fluids, cells, or tissue samples can be used to diagnose the presence of cancers, and in particular breast cancer.
- BCSGs may be measured alone in the methods of the invention, or, more preferably, in combination with other diagnostic markers for breast cancer including other BCSGs as described herein.
- the present invention provides methods for diagnosing the presence of cancer, and in particular breast cancer, by analyzing for changes in levels of BCSG in cells, tissues or bodily fluids from a human patient compared with levels of BCSG in cells, tissues or bodily fluids of preferably the same type from a normal human control, wherein an increase in levels of BCSG in the patient versus the normal human control is associated with the presence of cancer.
- a positive result indicating the patient being tested has breast cancer is one in which cells, tissues, or bodily fluid levels of a cancer marker, such as BCSG, are at least two times higher, and most preferably are at least five times higher, than in preferably the same cells, tissues, or bodily fluid of a normal human control.
- a cancer marker such as BCSG
- the present invention also provides a method of diagnosing metastatic cancer, and in particular metastatic breast cancer, in a patient having breast cancer which has not yet metastasized.
- a human cancer patient suspected of having breast cancer which may have metastasized (but which was not previously known to have metastasized) is identified. This is accomplished by a variety of means known to those of skill in the art.
- determining the presence of BCSG in cells, tissues, or bodily fluid is particularly useful for discriminating between cancers which have not metastasized and cancers which have metastasized.
- Existing techniques have difficulty discriminating between breast cancer which has metastasized and breast cancer which has not metastasized.
- proper treatment selection is often dependent upon such knowledge.
- one of the cancer marker levels measured in cells, tissues, or bodily fluid of a human patient is BCSG.
- Levels in the human patient are compared with levels of BCSG in preferably the same cells, tissue, or bodily fluid type of a normal human control. That is, if the cancer marker being observed is BCSG in serum, this level is preferably compared with the level of BCSG in serum of a normal human control .
- An increase in BCSG in the human patient versus the normal human control is associated with a cancer which has metastasized.
- a positive result indicating the cancer in the patient being tested or monitored has metastasized is one in which cells, tissues, or bodily fluid levels of a cancer marker, such as BCSG, are at least two times higher, and more preferably are at least five times higher, than in preferably the same cells, tissues, or bodily fluid of a normal human control.
- a cancer marker such as BCSG
- Normal human control includes a human patient without cancer and/or non cancerous samples from the patient; in the methods for diagnosing metastasis or monitoring for metastasis, normal human control preferably includes samples from a human patient that is determined by reliable methods to have breast cancer which has not metastasized, such as samples from the same patient prior to metastasis . Staging
- the invention also provides a method of staging cancers in a human patient.
- the method comprises identifying a human patient having breast cancer and analyzing a sample of cells, tissues, or bodily fluid from such patient for BCSG.
- the measured BCSG levels are then compared to levels of BCSG in preferably the same cells, tissues, or bodily fluid type of a normal human control, wherein an increase in BCSG levels in the human patient versus the normal human control is associated with breast cancer which is progressing and a decrease in the levels of BCSG is associated with breast cancer which is regressing or in remission.
- Moni taring Moni taring
- the method comprises identifying a human patient having breast cancer that is not known to have metastasized; periodically analyzing cells, tissues, or bodily fluid from such patient for BCSG; and comparing the BCSG levels in such cells, tissue, or bodily fluid with levels of BCSG in preferably the same cells, tissues, or bodily fluid type of a normal human control, wherein an increase in BCSG levels in the patient versus the normal human control is associated with breast cancer which has metastasized.
- the method comprises identifying a human patient having breast cancer; periodically analyzing cells, tissues, or bodily fluid from such patient for BCSG; and comparing the BCSG levels in such cells, tissue, or bodily fluid with levels of BCSG in preferably the same cells, tissues, or bodily fluid type of a normal human control, wherein an increase in BCSG levels in the patient versus the normal human control is associated with breast cancer which is progressing in stage and a decrease in the levels of BCSG is associated with breast cancer which is regressing in stage or in remission.
- Monitoring such patients for onset of metastasis is periodic and preferably done on a quarterly basis. However, this may be performed more or less frequently depending on the cancer, the particular patient, and the stage of the cancer.
- the methods described herein can further be utilized as prognostic assays to identify subjects having or at risk of developing a disease or disorder associated with increased levels of BCSG.
- the present invention provides a method in which a test sample is obtained from a human patient and BCSG is detected.
- the presence of higher BCSG levels as compared to normal human controls is diagnostic for the human patient being at risk for developing cancer, particularly breast cancer .
- the effectiveness of therapeutic agents to decrease expression or activity of the BCSGs of the invention can also be monitored by analyzing levels of expression of the BCSGs in a human patient in clinical trials or in in vi tro screening assays such as in human cells. In this way, the gene expression pattern can serve as a marker, indicative of the physiological response of the human patient, or cells as the case may be, to the agent being tested. Detection of genetic lesions or mutations
- the methods of the present invention can also be used to detect genetic lesions or mutations in BCSG, thereby determining if a human with the genetic lesion is at risk for breast cancer or has breast cancer.
- Genetic lesions can be detected, for example, by ascertaining the existence of a deletion and/or addition and/or substitution of one or more nucleotides from the BCSGs of this invention, a chromosomal rearrangement of BCSG, aberrant modification of BCSG (such as of the methylation pattern of the genomic DNA) , the presence of a non-wild type splicing pattern of a mRNA transcript of BCSG, allelic loss of BCSG, and/or inappropriate post- translational modification of BCSG protein.
- Methods to detect such lesions in the BCSG of this invention are known to those of skill in the art. Assay Techniques
- Assay techniques that can be used to determine levels of gene expression, such as BCSG of the present invention, in a sample derived from a human are well-known to those of skill in the art.
- Such assay methods include radioimmunoassays , reverse t ranscriptase PCR (RT-PCR) assays, immunohistochemistry assays, in si tu hybridization assays, competitive-binding assays, Western Blot analyses, ELISA assays and proteomic approaches, two-dimensional gel electrophoresis (2D electrophoresis) and non-gel based approaches such as mass spectrometry or protein interaction profiling.
- ELISAs are frequently preferred to diagnose a gene's expressed protein in biological fluids.
- An ELISA assay initially comprises preparing an antibody, if not readily available from a commercial source, specific to BCSG, preferably a monoclonal antibody.
- a reporter antibody generally is prepared which binds specifically to BCSG.
- the reporter antibody is attached to a detectable reagent such as a radioactive, fluorescent or enzymatic reagent, for example horseradish peroxidase enzyme or alkaline phosphatase .
- antibody specific to BCSG is incubated on a solid support, e.g., a polystyrene dish, that binds the antibody. Any free protein binding sites on the dish are then covered by incubating with a non-specific protein such as bovine serum albumin.
- a non-specific protein such as bovine serum albumin.
- the sample to be analyzed is incubated in the dish, during which time BCSG binds to the specific antibody attached to the polystyrene dish. Unbound sample is washed out with buffer.
- a reporter antibody specifically directed to BCSG and linked to a detectable reagent such as horseradish peroxidase is placed in the dish resulting in binding of the reporter antibody to any monoclonal antibody bound to BCSG. Unattached reporter antibody is then washed out.
- Reagents for peroxidase activity including a colorimetric substrate are then added to the dish.
- the amount of color developed in a given time period is proportional to the amount of BCSG protein present in the sample. Quantitative results typically are obtained by reference to a standard curve .
- a competition assay can also be employed wherein antibodies specific to BCSG are attached to a solid support and labeled BCSG and a sample derived from the patient or human control are passed over the solid support.
- the amount of label detected which is attached to the solid support can be correlated to a quantity of BCSG in the sample.
- nucleic acid methods can also be used to detect BCSG mRNA as a marker for cancer, and in particular breast cancer.
- PCR Polymerase chain reaction
- LCR ligase chain reaction
- NASABA nucleic acid sequence based amplification
- RT-PCR reverse-transcriptase PCR
- cDNA complementary DNA
- RT-PCR can thus reveal by amplification the presence of a single species of mRNA. Accordingly, if the mRNA is highly specific for the cell that produces it, RT-PCR can be used to identify the presence of a specific type of cell.
- Hybridization to clones or oligonucleotides arrayed on a solid support can be used to both detect the expression of and quantitate the level of expression of that gene.
- a cDNA encoding a BCSG gene is fixed to a substrate.
- the substrate may be of any suitable type including but not limited to glass, nitrocellulose, nylon or plastic.
- At least a portion of the DNA encoding the BCSG gene is attached to the substrate and then incubated with the analyte, which may be RNA or a complementary DNA (cDNA) copy of the RNA, isolated from the tissue of interest.
- Hybridization between the substrate bound DNA and the analyte can be detected and quantitated by several means including but not limited to radioactive labeling or fluorescence labeling of the analyte or a secondary molecule designed to detect the hybrid. Quantitation of the level of gene expression can be done by comparison of the intensity of the signal from the analyte compared with that determined from known standards . The standards can be obtained by in vi tro transcription of the target gene, quantitating the yield, and then using that material to generate a standard curve.
- 2D electrophoresis is a technique well known to those in the art. Isolation of individual proteins from a sample such as serum is accomplished using sequential separation of proteins by different characteristics usually on polyacrylamide gels. First, proteins are separated by size using an electric current. The current acts uniformly on all proteins, so smaller proteins move farther on the gel than larger proteins. The second dimension applies a current perpendicular to the first and separates proteins not on the basis of size but on the specific electric charge carried by each protein. Since no two proteins with different sequences are identical on the basis of both size and charge, the result of a 2D separation is a square gel in which each protein occupies a unique spot. Analysis of the spots with chemical or antibody probes, or subsequent protein microsequencing can reveal the relative abundance of a given protein and the identity of the proteins in the sample.
- Bodily fluids useful in the present invention include blood, urine, saliva, or any other bodily secretion or derivative thereof.
- Blood can include whole blood, plasma, serum, or any derivative of blood.
- BCSGs are also useful in the rational design of new therapeutics for imaging and treating cancers, and in particular breast cancer.
- antibodies which specifically bind to BCSGs can be raised and used in vivo in patients suspected of suffering from cancer.
- Antibodies which specifically bind a BCSG can be injected into a patient suspected of having cancer for diagnostic and/or therapeutic purposes.
- the preparation and use of antibodies for in vivo diagnosis is well known in the art.
- antibody-chelators labeled with Indium-Ill have been described for use in the radioimmunoscintographic imaging of carcinoembryonic antigen expressing tumors (Sumerdon et al . Nucl. Med. Biol . 1990 17:247-254).
- these antibody-chelators have been used in detecting tumors in patients suspected of having recurrent colorectal cancer (Griffin et al . J. Clin. One. 1991 9:631- 640) .
- Antibodies with paramagnetic ions as labels for use in magnetic resonance imaging have also been described (Lauffer, R.B. Magnetic Resonance in Medicine 1991 22:339-342).
- Antibodies directed against BCSGs can be used in a similar manner. Labeled antibodies which specifically bind a BCSG can be injected into patients suspected of having breast cancer for the purpose of diagnosing or staging of the disease status of the patient. The label used will be selected in accordance with the imaging modality to be used.
- radioactive labels such as Indium-Ill, Technetium-99m or Iodine-131 can be used for planar scans or single photon emission computed tomography (SPECT) .
- Positron emitting labels such as Fluorine-19 can be used in positron emission tomography.
- Paramagnetic ions such as Gadlinium (III) or Manganese (II) can be used in magnetic resonance imaging (MRI) . Localization of the label permits determination of the spread of the cancer. The amount of label within an organ or tissue also allows determination of the presence or absence of cancer in that organ or tissue.
- an antibody which specifically binds a BCSG can also have a therapeutic benefit.
- the antibody may exert its therapeutic effect alone.
- the antibody can be conjugated to a cytotoxic agent such as a drug, toxin or radionuclide to enhance its therapeutic effect.
- Drug monoclonal antibodies have been described in the art for example by Garnett and Baldwin, Cancer Research 1986 46:2407-2412. The use of toxins conjugated to monoclonal antibodies for the therapy of various cancers has also been described by Pastan et al . Cell 1986 47:641-648.
- Yttrium-90 labeled monoclonal antibodies have been described for maximization of dose delivered to the tumor while limiting toxicity to normal tissues (Goodwin and Meares Cancer Supplement 1997 80:2675-2680).
- Other cytotoxic radionuclides including, but not limited to Copper-67, Iodine- 131 and Rhenium-186 can also be used for labeling of antibodies against BCSG.
- Antibodies which can be used in these in vivo methods include polyclonal, monoclonal and omniclonal antibodies and antibodies prepared via molecular biology techniques.
- Antibody fragments and aptamers and single-stranded oligonucleotides such as those derived from an in vi tro evolution protocol referred to as SELEX and well known to those skilled in the art can also be used.
- the present invention also provides methods for identifying modulators which bind to BCSG protein or have a modulatory effect on the expression or activity of BCSG protein. Modulators which decrease the expression or activity of BCSG protein are believed to be useful in treating breast cancer.
- screening assays are known to those of skill in the art and include, without limitation, cell-based assays and cell free assays.
- Small molecules predicted via computer imaging to specifically bind to regions of BCSG can also be designed, synthesized and tested for use in the imaging and treatment of breast cancer. Further, libraries of molecules can be screened for potential anticancer agents by assessing the ability of the molecule to bind to the BCSGs identified herein. Molecules identified in the library as being capable of binding to BCSG are key candidates for further evaluation for use in the treatment of breast cancer. In a preferred embodiment, these molecules will downregulate expression and/or activity of BCSG in cells. Adoptive Immuno therapy and Vaccines
- Adoptive immunotherapy of cancer refers to a therapeutic approach in which immune cells with an antitumor reactivity are administered to a tumor-bearing host, with the aim that the cells mediate either directly or indirectly, the regression of an established tumor.
- Transfusion of lymphocytes, particularly T lymphocytes falls into this category and investigators at the National Cancer Institute (NCI) have used autologous reinfusion of peripheral blood lymphocytes or tumor- infiltrating lymphocytes (TIL) , T cell cultures from biopsies of subcutaneous lymph nodules, to treat several human cancers (Rosenberg, S. A., U.S. Patent No. 4,690,914, issued Sep. 1, 1987; Rosenberg, S. A., et al . , 1988, N. England J. Med. 319:1676-1680).
- the present invention relates to compositions and methods of adoptive immunotherapy for the prevention and/or treatment of primary and metastatic breast cancer in humans using macrophages sensitized to the antigenic BCSG molecules, with or without non-covalent complexes of heat shock protein (hsp) .
- Antigenicity or immunogenicity of the BCSG is readily confirmed by the ability of the BCSG protein or a fragment thereof to raise antibodies or educate naive effector cells, which in turn lyse target cells expressing the antigen (or epitope) .
- Cancer cells are, by definition, abnormal and contain proteins which should be recognized by the immune system as foreign since they are not present in normal tissues. However, the immune system often seems to ignore this abnormality and fails to attack tumors.
- the foreign BCSG proteins that are produced by the cancer cells can be used to reveal their presence.
- the BCSG is broken into short fragments, called tumor antigens, which are displayed on the surface of the cell. These tumor antigens are held or presented on the cell surface by molecules called MHC, of which there are two types: class I and II.
- MHC of which there are two types: class I and II.
- Tumor antigens in association with MHC class I molecules are recognized by cytotoxic T cells while antigen- MHC class II complexes are recognized by a second subset of T cells called helper cells.
- T cells secrete cytokines which slow or stop tumor growth and help another type of white blood cell, B cells, to make antibodies against the tumor cells .
- B cells white blood cell
- T cells or other antigen presenting cells (APCs) are stimulated outside the body ⁇ ex vivo) , using the tumor specific BCSG antigen.
- the stimulated cells are then reinfused into the patient where they attack the cancerous cells.
- the BCSG antigen may be complexed with heat shock proteins to stimulate the APCs as described in U.S. Patent No. 5,985,270.
- the APCs can be selected from among those antigen presenting cells known in the art including, but not limited to, macrophages, dendritic cells, B lymphocytes, and a combination thereof, and are preferably macrophages.
- autologous immune cells such as lymphocytes, macrophages or other APCs are used to circumvent the issue of whom to select as the donor of the immune cells for adoptive transfer.
- Another problem circumvented by use of autologous immune cells is graft versus host disease which can be fatal if unsuccessfully treated.
- DNA of the BCSG can be introduced into effector cells similarly as in conventional gene therapy. This can enhance the cytotoxicity of the effector cells to tumor cells as they have been manipulated to produce the antigenic protein resulting in improvement of the adoptive immunotherapy.
- BCSG antigens of this invention are also useful as components of breast cancer vaccines.
- the vaccine comprises an immunogenically stimulatory amount of an BCSG antigen.
- Immunogenically stimulatory amount refers to that amount of antigen that is able to invoke the desired immune response in the recipient for the amelioration, or treatment of breast cancer. Effective amounts may be determined empirically by standard procedures well known to those skilled in the art.
- the BCSG antigen may be provided in any one of a number of vaccine formulations which are designed to induce the desired type of immune response, e.g., antibody and/or cell mediated. Such formulations are known in the art and include, but are not limited to, formulations such as those described in U.S. Patent 5,585,103.
- Vaccine formulations of the present invention used to stimulate immune responses can also include pharmaceutically acceptable adjuvants.
- BCSGs Breast Cancer Specific Genes
- LIFESEQ Gold LSGold
- CLASP Cancer Leads Automatic Search Package
- the CLASP performs the following steps:
- the CLASP allows the identification of highly expressed organ and cancer specific genes. A final manual in depth evaluation is then performed to finalize the Organ Cancer Specific Genes
- BCSGs (OCSGs) selection.
- Table 1 provides the BCSGs of the present invention identified using CLASP.
- Table 1 BCSGs
- BCSG-5 SEQ ID NO : 5 , Clone ID 3040232, Gene ID 411152
- MAM009 MAM009
- Real-Time quantitative PCR with fluorescent Taqman probes is a quantitation detection system utilizing the 5'- 3' nuclease activity of Taq DNA polymerase .
- the method uses an internal fluorescent oligonucleotide probe (Taqman) labeled with a 5' reporter dye and a downstream, 3' quencher dye.
- Taqman internal fluorescent oligonucleotide probe
- the 5' -3' nuclease activity of Taq DNA polymerase releases the reporter, whose fluorescence can then be detected by the laser detector of the Model 7700 Sequence Detection System (PE Applied Biosystems, Foster City, CA, USA) .
- Amplification of an endogenous control is used to standardize the amount of sample RNA added to the reaction and normalize for Reverse Transcriptase (RT) efficiency.
- Either cyclophilin, glyceraldehyde-3 -phosphate dehydrogenase (GAPDH) or 18S ribosomal RNA (rRNA) was used as this endogenous control.
- GPDH glyceraldehyde-3 -phosphate dehydrogenase
- rRNA 18S ribosomal RNA
- RNA was extracted from normal tissues, cancer tissues, and from cancers and the corresponding matched adjacent tissues.
- first strand cDNA was prepared with reverse transcriptase and the polymerase chain reaction was done using primers and Taqman probe specific to each target gene.
- the results were analyzed using the ABI PRISM 7700 Sequence Detector.
- the absolute numbers are relative levels of expression of the target gene in a particular tissue compared to the calibrator tissue.
- Primers used for expression analysis include: BCSG-5 forward:
- Table 2 The absolute numbers depicted in Table 2 are relative levels of expression of BCSG-5 in 12 normal different tissues. All the values are compared to normal testis (calibrator) . These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals . Table 2 : Relative Levels of BCSG-5 Expression in Pooled Samples
- the relative levels of expression in Table 2 show that BCSG-5 mRNA expression is detected in the pool of normal mammary gland and in testis but not in the other 10 normal tissue pools analyzed.
- the level of expression in mammary gland is more than 100 fold higher than in testis.
- These results demonstrate that BCSG-5 mRNA expression is highly specific for mammary gland tissue and is also found in testis. Expression in a male specific tissue is not relevant in detecting cancer in female specific tissues.
- the absolute numbers in Table 2 were obtained analyzing pools of samples of a particular tissue from different individuals. They can not be compared to the absolute numbers originated from RNA obtained from tissue samples of a single individual in Table 3.
- the absolute numbers depicted in Table 3 are relative levels of expression of BCSG-5 in 78 pairs of matching samples.
- Table 3 Among 160 samples in Table 3 representing 17 different tissues significant expression is seen only in mammary gland tissues. These results confirm the tissue specificity results obtained with normal samples shown in Table 2.
- Table 2 and Table 3 represent a combined total of 172 samples in 21 human tissue types. One hundred and twenty samples representing 20 different tissue types excluding mammary gland had no detectable level of BCSG-5 mRNA. Other than mammary gland, BCSG-5 is detected only in one tissue type (testis) and then only in the pooled tissue sample (Table 2) but not in the matched testis cancer samples (Table 3; testis 1 and 2) .
- BCSG-5 is expressed at higher levels in 12 of 25 (48%) cancer samples (mammary gland 1, 2, 8, 10, 12, 13, 17, 19, 21, 22, 23 and 25) compared to normal adjacent tissue.
- Example 3 Determination of mRNA expression of BCSG-1 The mRNA expression level of BCSG, BCSG-1 (SEQ ID NO : 1 ,
- Gene ID 332369 also referred to as MAM014 were also determined in accordance with methods as set forth in Example
- Table 4 The absolute numbers depicted in Table 4 are relative levels of expression of BCSG-1 in 37 normal samples from 25 different tissues. All the values are compared to normal kidney (calibrator) . These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals; except for the blood samples that they are normal samples from a single individual . Table 4: Relative Levels of BCSG-1 Expression in Pooled Samples
- the relative levels of expression in Table 4 show that BCSG-1 mRNA expression is detected in the pool of normal mammary gland as well as in the other normal tissue analyzed.
- the absolute numbers in Table 5 were obtained analyzing pools of samples of a particular tissue from different individuals, except for the blood samples. They can not be compared to the absolute numbers originated from RNA obtained from tissue samples of a single individual in Table 5.
- Table 5 The absolute numbers depicted in Table 5 are relative levels of expression of BCSG-1 in 77 pairs of matching samples. All the values are compared to normal kidney (calibrator) . A matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual. In addition, 3 unmatched cancer samples (from ovary) and 3 unmatched normal samples (from ovary) were also tested. Table 5: Relative Levels of BCSG-1 Expression in Individual Samples
- Negative Table 5 represents 160 samples in 17 different tissues.
- Table 4 and Table 5 represent a combined total of 197 samples in 27 human tissue types. Comparisons of the level of mRNA expression in breast cancer samples and the normal adjacent tissue from the same individuals are shown in Table 5.
- BCSG-1 is expressed at higher levels in 27 of 30 (90%) cancer samples (mammary gland 1-7, 9-20, 22-25, 27-29, and 31) compared to normal adjacent tissue.
- BCSG BCSG-2 (SEQ ID NO: 2 or 18, Gene ID 480489), also referred to as MAM013 were also determined in accordance with methods as set forth in Example 2.
- RNA samples depicted in Table 6 are relative levels of expression of BCSG-2 in 37 normal samples from 25 different tissues. All the values are compared to normal liver (calibrator) . These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals, except for the blood samples that they are normal samples from a single individual.
- the relative levels of expression in Table 6 show that BCSG-2 mRNA expression is detected in the pool of normal mammary gland. The level of expression is higher than in the other tissues with the exception of two blood samples.
- the absolute numbers in Table 6 were obtained analyzing pools of samples of a particular tissue from different individuals, except for the blood samples. They can not be compared to the absolute numbers originated from RNA obtained from tissue samples of a single individual in Table 7.
- Table 7 The absolute numbers depicted in Table 7 are relative levels of expression of BCSG-2 in 76 pairs of matching samples. All the values are compared to normal liver (calibrator) . A matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual. In addition, 3 unmatched cancer samples (from ovary) and 3 unmatched normal samples (from ovary) were also tested. Table 7: Relative Levels of BCSG-2 Expression in Individual Samples
- Table 7 represents 158 samples in 17 different tissues. Table 6 and Table 7 represent a combined total of 195 samples in 25 human tissue types. Comparisons of the level of mRNA expression in breast cancer samples and the normal adjacent tissue from the same individuals are shown in Table 7. BCSG-2 is expressed at higher levels in 11 of 30 (37%) cancer samples (mammary gland 2-4, 8, 10, 11, 13, 14, 21, 27, 28) compared to normal adjacent tissue.
- BCSG, BCSG-3 SEQ ID NO: 3 or 20, Gene ID 274731
- MAM017 The mRNA expression level of BCSG, BCSG-3 (SEQ ID NO: 3 or 20, Gene ID 274731), also referred to as MAM017 were also determined in accordance with methods as set forth in Example 2.
- RNA samples depicted in Table 8 are relative levels of expression of BCSG-3 in 36 normal samples from 25 different tissues. All the values are compared to normal prostate (calibrator) . These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals, except for the blood samples that they are normal samples from a single individual.
- Table 9 The absolute numbers depicted in Table 9 are relative levels of expression of BCSG-3 in 68 pairs of matching samples. All the values are compared to normal prostate
- a matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual.
- 1 unmatched cancer sample (from ovary) and 1 unmatched normal sample (from ovary) were also tested.
- Table 9 represents 138 samples in 17 different tissues.
- Table 8 and Table 9 represent a combined total of 174 samples in 26 human tissue types.
- BSCG-3 is expressed at higher levels in 17 of 21 (81%) cancer samples (mammary gland 1, 3-6, 7-9, 11-16, 19-21) compared to normal adjacent tissue.
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US6844325B2 (en) | 1998-12-28 | 2005-01-18 | Corixa Corporation | Compositions for the treatment and diagnosis of breast cancer and methods for their use |
US6958361B2 (en) | 1998-12-28 | 2005-10-25 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of breast cancer |
US6969518B2 (en) | 1998-12-28 | 2005-11-29 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of breast cancer |
US6680197B2 (en) | 1998-12-28 | 2004-01-20 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of breast cancer |
US6586572B2 (en) | 1998-12-28 | 2003-07-01 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of breast cancer |
US6518237B1 (en) | 1998-12-28 | 2003-02-11 | Corixa Corporation | Compositions for treatment and diagnosis of breast cancer and methods for their use |
US6590076B1 (en) | 1999-04-02 | 2003-07-08 | Corixa Corporation | Compositions for the treatment and diagnosis of breast cancer and methods for their use |
US7598226B2 (en) | 1998-12-28 | 2009-10-06 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of breast cancer |
US6780586B1 (en) | 1999-11-29 | 2004-08-24 | Protein Design Labs, Inc. | Methods of diagnosing breast cancer |
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WO2000008210A1 (en) * | 1998-08-04 | 2000-02-17 | Diadexus Llc | A novel method of diagnosing, monitoring, staging, imaging and treating breast cancer |
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WO2000008210A1 (en) * | 1998-08-04 | 2000-02-17 | Diadexus Llc | A novel method of diagnosing, monitoring, staging, imaging and treating breast cancer |
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Title |
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DATABASE SWISSPROT [Online] Accession number P36537, 1 January 1994 (1994-01-01) JIN, C.-J. ET AL.: "cDNA cloning and expression of two new members of the human liver UDP-glucuronosyltransferase 2B subfamily" XP002267171 * |
JIN C_J ET AL: "cDNA cloning and expression of two new members of the human liver UDP-glucuronosyltransferase 2B subfamily" BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol. 194, no. 1, 15 July 1993 (1993-07-15), pages 496-503, XP002121839 ISSN: 0006-291X * |
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